Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease leading to ptosis, dysphagia, and proximal limb muscles at later stages. A short abnormal (GCN) triplet expansion in the polyA-binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. Here we demonstrate that treating mice with guanabenz acetate (GA), an FDA-approved antihypertensive drug, reduces the size and number of nuclear aggregates, improves muscle force, protects myofibers from the pathology-derived turnover and decreases fibrosis. GA targets various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. We demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data show that modulation of protein folding regulation is beneficial for OPMD and promote the further development of GA or its derivatives for treatment of OPMD in humans. Furthermore, they support the recent evidences that treating ER stress could be therapeutically relevant in other more common proteinopathies.

Ergogenic Effect of BCAAs and L-Alanine Supplementation: Proof-of-Concept Study in a Murine Model of Physiological Exercise

“…This is in line with previous observations that showed that BCAAs and ALA, when individually administered, exert a potent anti-inflammatory effect in both exercised animal models and athletes [29,48], and that IL-6 release can be modulated by nutritional interventions in trained subjects, with either BCAAs or ALA reducing post-exercise levels of this cytokine by 40% [49]. The ability to control inflammatory response may also help to preserve the equilibrium of BCAAs metabolism, since inflammation and endoplasmic reticulum stress play a critical role in regulating BCAAs uptake in adipocytes and muscle tissue [50,51].…”

Inhibition of Myostatin Reduces Collagen Deposition in a Mouse Model of Oculopharyngeal Muscular Dystrophy (OPMD) With Established Disease

“…It is reported that the disease progression manifests as visible changes in muscle mass at 18 weeks of age in the model mice (Trollet et al, 2010). Recent efforts to ameliorate symptoms have focused on small molecule approaches to target protein aggregation and gene therapy approaches to correct the mutation (Malerba et al, 2017(Malerba et al, , 2019a. In our previous study we showed that the administration of the RK35 antibody counteracted the muscle atrophy and improved histopathological features of the disease (Harish et al, 2019).…”

“…Whole muscle images (for laminin based fiber morphometry) or random fields (for PABPN1 and collagen immunostaining) were captured using a microscope (Zeiss, United Kingdom). For analysis of fiber morphometry, the median minimal feret's diameter from 1000 randomly selected fibers were determined for TA muscles for each individual animal analyzed (Harish et al, 2019;Malerba et al, 2019a). For picrosirius red staining, sections were air dried, fixed in PFA 4%, and stained in a 0.3% solution of Sirius red in saturated aqueous picric acid, followed by a treatment with 0.5% acetic acid.…”

“…Here, we show that administration of the anti-myostatin monoclonal antibody RK35 to 42 week old A17 mice for a period of 10 weeks, while not affecting accumulation of intranuclear aggregates, or loss of body mass, muscle atrophy, or muscle strength, does, however, reduce deposition of fibrotic collagen proteins. This would suggest the proposed anti-myostatin therapy may have a role as an adjuvant treatment option in established disease states in addition to gene therapy or small molecule strategies to ameliorate disease symptoms and presents future avenues to be investigated (Malerba et al, 2017(Malerba et al, , 2019a.…”

scLink: Inferring Sparse Gene Co-expression Networks from Single-cell Expression Data

“…In this module, three edges (Jund-Fos, Fosb-Fosl2, Fosl1-Fosl2) are only identified by scLink. In addition, the network also contains a four-gene module involved in muscle regeneration [61,62] and a five-gene module which was shown to play roles in myoblast differentiation [63,64,65]. These two modules are also missed by the classic correlation approach.…”